Phenthiazine derivatives and processes for their preparation



United States Patent M 3,150,129 PHENTHIAZINE DERIVATIVES AND PROCESSESFOR THEIR PREPARATION Robert Michel Jacob, Ablon-sur-Seine, and JacquesGeorges Robert, Gentilly, France, assignors to Rhone- Poulenc S.A.,Paris, France, a corporation of France No Drawing. Filed Apr. 5, 1962,Ser. No. 185,194

Claims priority, application France Oct. 21, 1957 1 Claim. (Cl. 260243)This invention relates to new phenthiazine derivatives and to theirpreparation. This application is a continuation-in-part of applicationSerial No. 767,797, filed October 17, 1958, now United States Patent No.3,075,976.

During especially the past decade, considerable research andexperimentation have been conducted in the field of N-substitutedphenthiazine derivatives and certain of these compounds have been foundto possess valuable therapeutic properties. Some are useful primarily onaccount of outstanding antihistaminic activity, others because of theirunusually powerful effect as potentiators of drugs which act upon thenervous system and of their efficacy as antishock agents and yet others,for example, are effective agents for controlling or minimisingmotion-sickness. It has nevertheless been demonstrated that of the verylarge number of possible N-substituted phenthiazine compounds that havebeen proposed or tested by various workers, only comparatively few typeshave useful application in human or veterinary medicine and that boththe nature and the degree of useful effect can radically alter even withapparently small changes in chemical structure.

It is an object of the present invention to provide a new phenthiazinederivative, and its acid addition salts, which possess unexpectedlyuseful pharmacological properties. It is a further object of theinvention to provide processes for the preparation of the new compoundand its acid addition salts.

According to the present invention there is provided, as a new chemicalcompound, the compound 3-methylthio- 1O [3 (4hydroxymethyl-l-piperidyl)propyl]phenthiazine, which has the formula:

N SCHs l cHT-oHZ-oHFIOonmH and the acid addition salts thereof havingtherapeutically acceptable anions.

The said compound, and its said acid addition salts are valuablethereapeutic substances. In particular they are valuable neurolepticsand have in addition an exceptional anti-emetic activity.

The basic compound may be prepared, for example, by interaction of aphenthiazine derivative of the formula:

where Y represents the acid residue of a reactive ester,

3,150,129 Patented Sept. 22 1964 such as a halogen atom or a sulphonicor sulphuric ester, with 4-hydroxymethylpiperidine of the formula:

The aforesaid reaction may be carried out with or without a solvent inthe presence or absence of an alkaline condensing agent and optionallyat an elevated temperature. The preferred condensing agents are alkalimetals and their amides or hydrides.

For therapeutic purposes the new compound of this invention, 3methyLthiO-IO-[3-(4-hydroxymethyl-1-piperidyl)propyl]phenthiazine, maybe used as such or in the form of non-toxic acid addition salts, i.e.,salts which have therapeutically acceptable anions in the sense that theanions are relatively innocuous to the animal organism in therapeuticdoses so that the beneficial physiological properties inherent in thebases are not vitiated by side effects ascribable to the anions.Suitable such salts are, for example, the hydrochlorides and otherhydrohalides, phosphates, nitrates, sulphates, maleates, fumarates,citrates, tartrates, methanesulphonates and ethanedisulphonates.

The following example will serve to illustrate the production of thecompound according to the invention:

Example 3 methylthio-lO-(3-methanesulphonyloxypropyl)phenthiazine (13.5g.) and 4-hydroxymethyl piperidine (6.9 g.) in toluene cc.) were heatedunder reflux for seven hours with stirring. The reaction mixture wasallowed to cool and water (50 cc.) was added. The resulting toluenesolution layer was decanted and washed twice with water (each 25 cc.).The toluene solution was then stirred with 5% hydrochloric acid cc.).The hydrochloride of the desired phenthiazine base precipitated in gummycondition in the aqueous layer. This was decanted and treated withsodium hydroxide (25 cc., density 1.33). It was then extracted threetimes with ethyl acetate (50 cc., 25 cc., and 25 cc.). The extracts weredried over sodium sulphate, filtered and concentrated in vacuo. Aresinous product (6.5 g.) was obtained.

This product was dissolved in a mixture of benzene (80 cc.) andcyclohexane (80 cc.) and chromatographed on a column containing 50 g.alumina. The chromatographed product was eluted successively withmixtures of benzene and cyclohexane and then with benzene and finallywith a mixture of benzene and ethyl acetate. The eluates were evaporatedto yield a crude product, M.P. 102l08 C. This product was recrystallisedfrom aqueous ethanol (40% Water) and yielded 3-me'thylthio-10- [3 (4hydroxymethyl-l-piperidyl)propyl]phenthiazine (4 g.) as white crystals,M.P. 108 C.

The starting material,3-methylthio-10-(3-methanesulphonyloxypropyl)phenthiazine, was obtainedby condensing methanesulphonyl chloride in anhydrous pyridine with3-methylthio-10 (3 hydroxypropyl)phenthiazine. This latter compound wasitself prepared by the action of hydrochloric acid in ethanol onB-methylthio-lO-(3-tetrahydropyranyloxy-propyl)phenthiazine, itselfprepared by condensing 1-chloro-3-tetrahydropyranyloxy propane with3-methylthio-phenthiazine (M.P. C.) in xylene in the presence ofsodamide.

All the intermediate products may be used in crude or resinouscondition.

We claim:

A compeund selected from the class consisting of 3- methylthio-IO-[3-(4-hydroxymethyl-1-piperidyl)propyl] phenthiazine of theformula:

CIIQOH and the acid addition salts thereof having therapeuticallyacceptable anions.

References Cited in the file of this patent UNITED STATES PATENTSGulesich et a1 Mar. 15, 1960 Jacob et al Jan. 29, 1963 FOREIGN PATENTSBelgium May 22, 1957 Belgium Oct. 31, 1957

